Methamphetamine (METH) is a drug of abuse with pronounced effects on the CNS including psychomotor activation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged used has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that METH produces long-lasting neurotoxic effects in the CNS. However, the exact mechanisms by which METH damages dopamine neurons are unknown. Excitatory amino acids such as glutamate have been implicated in the METH-induced depletions of dopamine. The primary objective of this proposal is to elucidate the factors underlying METH toxicity and focuses on the glutamate-dependent mechanisms and responses mediating the toxic effects of METH to striatal dopamine neurons. Pharmacological manipulations of glutamate transmission and in vivo measures of extracellular concentrations of dopamine and glutamate using microdialysis will be employed. In addition, the cellular responses to METH and glutamate-induced neurotoxicity will be assessed by measuring spectrin breakdown, hydroxyl radical formation, and lipid peroxidation. The first series of experiments will evaluate whether alterations in extracellular glutamate concentrations affect METH-induced striatal dopamine depletIons. The second specific aim will be to disrupt corticostriatal glutamatergic transmission by lesioning the ventral thalamic nuclei. The effects of these lesions on METH induced increases in striatal extra cellular glutamate concentrations and its long term effects on striatal dopamine content and tyrosine hydroxylase immunoreactivity will be determined. The third and fourth specific aims will determine the cytotoxic consequences of the increased extracellular concentrations of dopamine and glutamate by measuring the degree of spectrin proteolysis, the production of hydroxyl free radicals and their attendant neurotoxic effects indicated by lipid peroxidation. The final aim will be to evaluate the effects of repeated stress episodes and repeated administrations of low doses of METH or corticosterone on the subsequent neurotoxic effects of METH to dopamine neurons in forebrain regions. Overall, these experiments have significant clinical implications for the influence of toxic excitatory amino acids, environmental stressors, and/or prior drug exposure as determinants and consequences of drug-induced neurotoxicity. Since stress has a strong influence on the susceptibility to self administer amphetamine, these studies are also relevant to the consequences of prior exposure to neurotoxic doses of METH on drug seeking behavior and the reactivity to stressful events.